1-(lower alkyl)-4-phenyl-4-(tertiaryaminoalkoxymethyl- and tertiary-aminoalkoxy) piperidines and their preparation



like.

United States Patent l-(LOWER ALKYL)-4-PHENYL-4-'('IERTIARY- AMINOALKGXYMETHYL- AND TERTI- ARY-AMINOALKOXY) PWERIDINES AND THEiR- PREPARATIGN Bill Elpern, Albany, N. Y., assignor to Steriing Drug-Inc, New York, N.-Y., a corporation of Delaware 'No Drawing. Application June 4, 1953,

Serial No. 359,637

17 Claims. (Cl; 260247.'7)

This invention relates to l-(lower alkyl)-4-phenyl-4- (tertiary-aminoalkoxy-' and tertiary-aminoalkoxymethyl) piperidines, to their salts, and to the preparation of these compounds.

My new compounds in their free base form have .the general formula where n is-zero or one, X is a loweralkylenewradical whose twofree valence bonds are on .differentcarbon atoms, -NRRi is a tertiary-amino radical'vand=Rz is a lower alkyl radical. These piperidine derivatives ofmy invention have been "found topossessuseful pharmacological properties, in particular, analgesic activity.

- ln-the above general formula the lower alkyleneradical designated as X has two to fourcarbon-atoms, including such-examples as and thelike. The tertiary-amino radical, shown above as NRR1, comprehends' dialkylamino radicals where: Raand R1: are lower alkyl groups, alike or :difierent, and each alkyl. group has one to sixcarbon atoms, such dialkylamino radicalsincluding dimethylamino, diethylamino,

ethylmethylamino, diisopropylamino, ethyl-nepropylamino, di-n-butylamino, di-n-hexylamino, and the like. Further, the tertiary-aminoradical designated as NRRl .encompasses saturated 'N-heteromonocyclic radicals having five to six ring atom's,illustrated by examples such as 1- piperidylj (lower alkylated)-1-piperidyl such as 2-.methyl- .1p.ip'e'ridyl, 3rethyl-l-piperidyl, 4-methyl-1-piperidyl, 2,6- dimethyl-lapiperidyl; l-pyrrolidyl; (loweralkylatd)-1- pyrrolidyl 'such as Z-methyl-l-pyrrolidyl,'3-ethyl-1-pyrrolidyl, 2,5-dimethyl-l-pyrrolidyl; i-morpholinyl; andthe R2, the lower alkyl radical,- has 011611081X 7081" bon atoms, including such radicals asmethyl, ethyl, npro'pyl," n-butyl, isobutyl, 2-butyl, n-amyl, isoamyl, nhexyl, and the like.

The l-(lower alkyl)-4-phenyl-4 (tertiary-amindalkoxyand tertiary-aminoalkoxymethyl)piperidines of my'invention were prepared byheating an alkali metal salt of a l-(lower. alkyl)-4-phenyl-4-piperidinol or -4-pipe ridinemethanol'with a t'ertiary-aininoalkyl halide of the formula halogen-X-NRRr. illustrations of this process are the preparations of l-ethyl-4-pheny-l-4-(Z-diethylaminoethoxymethybpiperidine or 1-ethyl-4-phenyl-4r(lediethylaminoethoxy)piperidine ,by heating the sodiumsalt of --1--'ethyl- 4iphenyl-4-jpiperidinemethanol' or. -1-.ethyl- 4-phenyl-j4-piperidinol with Z-diethylaminoethylchloride. ..In.-practic- 2,773,870 Patented Dec. 11, 1956 ing my invention I found it convenient to use the tertiaryaminoalkyl'halide in the form of its hydrohalide salt, the acid portion of which was neutralized by excess sodium amide, the reagent I preferred to use in forming the alkali salt of the intermediate 4-piperidinol or 4-piperidine-- methanol.

. Preferred embodiments of my invention are quaternary ammonium salts of .the above defined l-(lower alkyl)-4- phenyl-4-.(tertiary-aminoalkoxyand tertiary-.aminoalkwhere nX',.R2 andNRR'i have the meanings given'above,

R's'is alo'wer alkyl radical or a benzyl radical and Anis a non-toxic anion. These. quaternary ammonium salts have been found to have curarimimetic and ganglionic .blockingaproperties.

In the above formula, R3 is a lower alkyl radical hav- ..i ng. one to six .carbon atoms, including such radicals as. methyl, .ethyl, npropyl,,isopropyl, n-butyl, .isobutyl, 2-buty1, n-amyl, isoamyl, n-hexyl, and, the like. L. .The nontoxic anion, designated as An, which can beany, anion,

for instance, chloride, bromide, iodide, sulfate, benzene- "s'uifonate, para-.toluenesulfonate,and the like, has noappreciable pharmacological activityof its own inthe, high dilutions at which .the quaternary ammonium salts as a whole are effective. .In particular, the anions contribute nothing to the ganglionic blocking or curarimimetic activity which 'resides solely in the remainder of the molecule.

Thus, my'invention .comprehends, as the preferred em- "b-odimenn'quaternary. ammonium salts of the above defined 1 (lower 'alkyl)-4-phenyl-4-(tertiary-aminoalkoxyand tertiaIy-aminoalkoxymethyl):piperidines, said salts being prepared by'treating my piperidines with a lower alkyl or benzyl ester of an acid, either inorganic or organic, such esters having the formulaflRsAn and including methyl iodide, methyl bromide, ethylchloride, ethyl *bromide, ethyl sulfate, n-propyli-odide, benzyl chloride,

pana-nitrobenzyl chloride, :para-chlorobenzyl chloride,

methyl paratoluenesulfonate, ethyl para-toluenesulfonate, ethyl benzenesulfonate, and'the like, the respective quaternary salts being the methiodides, methobromides, etho- -chlo'rides, ethobromides, ethosulfates, n-propi-odides, benzochlorides, para-nitrobenzochlorides, .parachlorobenzo chlorides, metho-para-toluenesulfonates, ethopara-toluenesulfonates, 'ethobenzenesulfonates, and. the like.

Sometimes direct addition of an ester, RaAn, to the 1- lower alkyl)-4-phenyl-4-(tertiary-aminoalkoxyor, ter- I tiary-aminoalkoxymethyl)-piperidine does not occur read- "ily (111810 the properties of the particular esterused. This -is-.-the case if the anion, A11, is derived from a relatively weakacid. such as citric acid or tartaric'acid. In ,such "cases it is possible by use of metathetical reactions; to replace the anion without 'reconversion to ,the tertiary amine. This is usually effected by treatment-ofan aqueious solution of the quaternary ammonium salt QAn,

with silver oxide (hydroxide). The silver saltgAgAn, is precipitated, leaving in solution the quaternary ammoniumhydroxide, QOH. It is prerequisite, .of. course,

that the salt AgAn be insoluble. in' water. The quaternary ammonium hydroxide may then be neutralized with the appropriate acid, 'HAn, {01 give any desired salt. For example, methi'odides are generallyeasier to prepare by respective methocitrate or methotartrate is obtained. My invention also comprehends acid addition salts of the above described l-(lower alkyl)-4-phenyl-4-(tertiaryaminoalkoxyand tertiary aminoalkoxymethyl)piperidines, such salts being prepared by treating the basic piperidine derivatives with the appropriate acid. Included among such acid addition salts are the following, formed by reacting the basic piperidine compound with the appropriate relatively non-toxic, inorganic or organic acid: the hydrochloride, hydrobromide, hydroiodide,

phosphate, sulfate, sulfamate, ethanesulfonate, tartrate,

citrate, succinate, acetate, benzoate, oleate, and the like. The compounds of my invention are further illustrated by the following examples without however being limited thereto.

EXAMPLE 1 Methyl iodide re- 1-met fryl-4-phenyl-4- [2-(1 -piperidyl) ethoxymethyllpiperidine To'1.95 g. of sodium amide suspended. in 200 ml. of dry toluene was added 10.2 g. of 1-methyl-4-phenyl-4- piperidinemethanol and the resulting mixture refluxed until complete solution was elfected. The solution was cooled slightly and then there was added another 1.95 g.

portion of sodium amide followed by 9.2 g. of 2-(1- piperidyDethyl chloride hydrochloride. The resulting mixture was refluxed for about three hours or until evolution of ammonia ceased. It was then cooled and 50 ml.

of water was added carefully to dissolve any unreacted sodium amide and the sodium chloride that had separated. The organic layer was separated and washed with water. The aqueous layer was extracted with benzene and the extracts combined with the organic layer. The

resulting solution was filtered and the solvent removed by distillation in vacuo. Fractional distillation of the residual material yielded the product, 1-methyl-4-phenyl-4- [2-(l-piperidyl)ethoxymethyllpiperidine, B. P. 224-225 C. at 12 mm., n 1.5251.

Analysis.--Calcd. for CzoHazNzO: C, 75.90; H, 10.20; N, 8.85. Found: C, 75.84; H, 10.29; N, 8.68.

1 methyl-4-phenyl 4-[2-(l-piperidyl)ethoxymethylh piperidine,.in the form of its hydrochloride salt (prepared by dissolving the base in 0.1 1N aqueous HCl and adjusted the pH to about 5.5 using 0.1 NaOH), was found to have analgesic activity in the aminopyrine range when tested by the radiant thermal stimulation tests in rats.

Other l-(lower allkyl)-4-phenyl-4-(tertiary-aminoalkoxymethyD-piperidines can be prepared according to the foregoing procedure using the appropriate l-(lower alkyl) 4-phenyl-4-piperidinemethanol and tertiary-aminoalkyl halide, such compounds including the following: l-isopropyl-4-phenyl-4- [2-(3-ethyl-1-piperidyl) ethoxymethyl] piperidine,1 methyl-4-phenyl-4[3-( l-pyrrolidyl)propoxymethyl]piperidine, 1-e thy1-4-phenyl-4- [2-(2,5-dimethyl- 1- pyrrolidyl)ethoxymethyllpiperidine, 1-methyl-4-phenyl-4 [4 (1 piperidyl)butoxymethyllpiperidine, l-n-hexyl-4- phenyl-4-[3-(1-piperidyl)-propoxymethyl]piperidine, and the like. 1

EXAMPLE 2 1 methyl 4 phenyl 4 (2 diethylamirwethoxy methyl)piperidine This preparation was carried out following the proceduredescribed in Example 1, using 10.2 g. of l-methyldry benzene and 10 -ml.--of methyl iodide.

4-pl1enyl-4-piperidinemethanol, 8.6 g. of Z-diethylaminoethyl chloride hydrochloride, 3.90 g. of sodium amide (added in two equal portions as above) and 200 ml. of dry toluene. There was thus obtained 1-methyl-4-phenyl-4- (Z-diethylaminoethoxymethyl)-piperidine, B. P. 174-176 C. at 3.5 mm., n 1.5138.

Analysis.Calcd. for C19H32N2O: C, 74.94; H',l0.59; N, 9.22. Found: C, 74.53; H, 11.00; N, 8.99.

1 methyl 4-phenyl 4-(2-diethylaminoethoxymethyl) piperidine, in the form of its hydrochloride salt (prepared by dissolving the base in 0.1 1N aqueous HCl and adjusted the pHto about 5.5 using 0.1 NaOH), was found to have anglesic activity in the aminopyrine range when tested by the radiant thermal stimulation tests in rats.

Other compounds which can be prepared according to the above procedure include the following: 1-methyl-4- phenyl 4-(4-dimethylaminobutoxymethyl)piperidine, 1- ethyl 4 phenyl 4 (3 diethylamino 2 methylpropoxymethyl) piperidine, l-methyl-4 phenyl 4-(2-di-nbutylaminoethoxymethyl) piperidine, 1 isobutyl 4 phenyl 4( 3 diethylaminopropoxymethyl)piperidine, and the like.

EXAMPLE 3 1 methyl 4 phenyl 4 [2 (1 piperidyhethozcymethyl] piperidine dimethiodide A solution of 6.5 g. of 1-methy1-4-phenyl-4- [2-(l-piper idyl)ethoxymethyllpiperidine (prepared as in Example 1) in about 25 ml. of dry benzene was treated with an excess of methyl iodide (about 10 ml.). that separated was recrystallized several times from ethanol, yielding the product 1-methy1-4-phenyl-4-[2-(lpiperidyl)ethoxymethylJpiperidine dimethiodide, M. P. 240-2416 C.

Analysis.-Calcd. for CzzHsaIzNzO: C, 44.00; H, 6.38; I, 42.28. Found: C, 43.88; H, 6.38; I, 41.89.

When the procedure described above for the preparation of 1 methyl 4 phenyl 4 [2 (1 piperidylf ethoxymethyllpiperidine dimethiodide is followedusing methyl bromide, ethyl chloride, n-propyl iodide, benzyl Following the above procedure for the preparation of 1 methyl 4 7 phenyl 4 [2 (1 piperidyl)ethoxymethyllpiperidine dimethiodide using the appropriate piperidine derivative in place of 1 methyl 4 phenyl- 4 [2 (l piperidybethoxymethyl]piperidine, there can 'be obtained the following quaternary salts: l-isopropyl- 4 phenyl 4 [2 (3 ethyl 1 piperidyDethoxymethyllpiperldine dimethiodide, 1-methyl-4-phenyl-4-[3- l-pyrrolidyl)-propoxymethyl1piperidine dimethiodide, 1- ethyl 4 phenyl 4 [2 (2,5 4 dimethyl 1 -pyrrolidyl)ethoxymethyllpiperidine dimethiodide, 1-methy1-4- phenyl 4 [4 -(l piperidyl)butoxymethyflpiperidine,

dimethiodide, 1 n hexyl 4 phenyl- 4 [3 -'(1- piperidyl)propoxymethyllpiperidine dimethiodide, and the like.

0 EXAMPLE 4 1 methyl 4 -,phenyl 4 (2 diethylaminoethoxy I methyl) piperidine dimethiodide This compound, M. P. 208.4-209.5 C. (con), was

prepared following the procedure described in Example 3 using a solution of 6.75 g. of 1-methyl-4-p henyl-4- (2- diethylaminoethoxymethyl)piperidine in about 25 ml. of

The precipitate d a ys sfila d. or CmHashNzO: G. 2-87;. 65. 1.43.14. Found: C, 42.71; H, 6157; 1,42 .85.

other a l. y -phenyI- -(d a lsy m n alkoxymethyDpiperidine dimethioclijdes which can be'prepared according to the foregoing procedure include the following: 1-methyl 4-phenyl-4-(4-dimethylaminobutoxymethyl)piperidine dimethiodide, 1-ethyl-4-phenyl 4 (3-diethylamino-Z-methylpropoxymethyl)piperidine dimethiodide, 1-methyl-4-phenyl-4.(2;-di-' n butylaminoethoxymethyl)- piperidine dimethiodide, l-isobutyl-4-phenyl 4-(3-diethylaminopropoxymethyl)piperidine dimethiodide, and the like.

EXAMPLE 5 1-methyl-4-phenyl-4-(Z-dimethylaminoethoxymethyl)- piperidine dimethiodide The preparation of l-methyl-4pheuyl-4-(Z-dimethylaminoethox-ymethynpiperidine was carried out following the-proceduredescribed in Example 1 using'8.2 gxof, 1-methyl-4-phenyl-4-piperidinemethanol, 5.7.6 g. of 2-dimethylaminoethyl chloride hydrochloride, 3.54-g. of sodium amide (added in two equal'por-tions') and 150 ml. of dry toluene. Eight grams of this compound was obtained as a yellowv oil following removal of the benzene and toluenefrom thereaction mixture bydistilling in vacuo.

One-half of the oily l-methyl-4-phenyl-4-(2=dimethylaminoethoxymethyl)piperidine was dissolved in enough dry benzene to make 25 ml. of solution which was treated with 10 ml. of methyl iodide. The white oily material that separated solidified to a porousmass on cooling. This solid was collected and recrystallized once from methanol-iSPIQpanol, once, fromethanol, and once from. ri opa'nc yi ing he. prod c 1-me hy l-Pheriy j- (2r irine yl' i y hy )p p ridine dimethi'o i e, MZ P. 243.8-2457" C. (cor).

AnalysisCalcd. for C19I3412N2Q1 C, '40.69 H, 6.12; I, 45.30. Found C. 40.95 H, 6.24; I, 45.30.

EXAMPLE 6 1-meZhyl-4-phenyF-4- [2- (4-m0rpholinyl) ethoxymethyllpiperidine dimethiodide This preparation was carried out following the procedure described in Example 5, using 10.2 g. of 1-methyl-4- phenyl-4-piperidinemethanol, 9.3 g. of 2-(4-morpholinyl)- ethyl chloride hydrochloride, 9.7 g. of sodium amide and 200 ml. of dry toluene. There was thus obtained as a yellow oil, g. of l-methyl-4-phenyl-4-[2-(4-morpholinyl) ethoxymethyllpiperidine whichwas dissolvedin 100 1111, of acetone and the resulting Solution treated with 15 ml. of methyl iodide. The product that separated was collected and recrystallized several times from ethanol, yielding the product, 1-rnethyl-4-phenyl54-[2-(4-morpholinyl)ethoxymethyllpiperidine dimethiodide, M. P. 249- 250" C. (con). I

AnalysisCalcd. for C21H36I2N2O2: C. 41.87; H, 6.02; I, 42.14. Found: C, 41.95; H, 6.18; I, 41.80.

EXAMPLE 7 1-methyl-4-phenyl-4- [3-(1-piperidyl) propoxymethyl] piperidine dimethiodide from water-ethanol; yielding 1-methyl-4 -phenyl-4'-[3-(1;

3. The viscous, residual oil (7 g.) was fractionally distilled,

6 piperidyl)propoxymethyllpiperidine dimethiodide, M. P, 270i4 272.5'f"..(Qr.-). I

Analysis -Calcd. forCzaI-lmIzNzO: C, 44.96; H; 6.56; I, 41.31. Found: C, 45.15; H, 6.47; I, 40370.

The 1 (lower alkyl)=4 phenyl-4-(tertiary-aminoalkoxy methyl)p iperidine quaternary salts of Examples -37 when tested for curarimimeticactivity in mice using the inclinedscreen test were found to have EDSO's of about 5 to 20- mg./kg. and when tested for ganglionic blocking activity in anesthetized'dogs'were found to be from two to eight times as effective as tetraethylammonium bromide in blocking each of the parasympathetic and sympathetic ganglia. The acute toxicities (LD50) of these quaternary salts when tested subcutaneously in mice werejfoundto befrom about 14' to 62 mg./ kg.

EXAMPLE "8 1-methyl-4-phenyl-4-[2 (1-piperidyl) ethoxylpiperidine cooled to about 30 C. and 50 ml. of water wasadded carefully-with stirring to dissolve any unreacted sodium amide and the sodium chloride that hadseparated. The organic layer was separated, washed with water and distilled in vacuo onagsteam bath to remove the solvent.

, oxylpiperidine, 1-methyl-4-phenyl-4-[2-(4-morpholinyl) ethox-ylpipcridine, and the like.

EXAMPLE 9 1-methyi-4-phenyl-4 [2- (I-piperidyl) ethoxylpiperidine dimeth iodide A solution of 5.5 g. of l-methyl-4-phcnylr4-[2-(l-piperidyl)ethoxylpiperidine in 150 ml. of ethyl acetate was treated with 10 ml. of methyl iodide. The resulting crystalline precipitate was collected, washed with ethyl acetate and recrystallized once from absolute ethanol and once from methanol-ethanol. The resulting product, 1-

methyl-4-phenyl-4- [2-( l-pipcridyl) ethoxyl piperidine dimethiodide, M, P. 251=.5252.5' C. (con). 1 AnalysisCalcd. for C21H3sI2N2O: C, 43.01; H, 6.19;

I, 43.29. Found: C, 43.22; H, 6.17; I, 43.08.

1-methyl-4-phenyl-4- [2 l-piperidyl ethoxy] piperidinedimethiodide when tested for curarimimetic activity in mice using the incline screen test was found to havean ED50 of :7 rug/kg. and when tested for ganglionic blocking activity in anesthetized dogs was found to be one-half as effective as tetraethylammonium bromide in blocking each of the parasympathetic and sympathetic ganglia. The activity toxicity (ALDso) of l-methyl-4- phenyl-4- [2-( l-piperidyl ethoxyl piperidine dimethiodide when tested subcutaneously in mice was found to be about 280 mg./kg.

When the procedure described above for the preparation of l-methyl-4-phenyl-4- [2-(1-.piperidyl)ethoxylpiperidine dimethiodide is followed using methyl bromide,

ethyl chl oride, n-propyl iodide, benzyl chloride or ethyl para-toluenesulfonate in 'place of methyl iodide, there is: 1

idene dimethiodide, l-methyl-4-phenyl-4-[2-(2,5-dimeth---' yl-l-pyrrolidyl)ethoxylpiperidine dimethiodide, l-isobutyl 4 'p-henyl 4 [3 (1' pyrrolidyDpropoxylpiperidine dimethiodide, 1-methyl-4-phenyl-4-[2-(4-morpho linyl)ethoxy]piperidine dimethiodide, and the like.

' I claim:

1. A member of the group consisting of a compound. having the formula )OHzh-O-X-NRRr c on, om 2 (EH: (IJH:

where n is selected from the group consisting of Zero and one, X is a lower alkylene radical having from 2 to 4 carbon atoms whose two free valence bonds are on different carbon atoms, NRR1 is a member of the group consisting of lower dialkylamino, l-piperidyl, (lower,

alkylated)-1-piperidyl, l-pyrrolidyl, (lower alkylated)- l-pyrrolidyl and 4-morpholinyl, and R2 is a lower alkyl radical and its acid addition and di-quaternary ammonium salts.

2. A quaternary ammonium salt of a l-(lower alkyl)- 4-phenyl-4-(dialkylaminoalkoxymethyl)piperidine having the formula where X is a lower alkylene radical having from 2 to 4 carbon atoms whose two free valence bonds are on different carbon atoms, and R2 and R3 are each lower alkyl radicals, and An is a non-toxic anion.

3. A quaternary ammonium salt of a l-(lower alkyl)- 4- phenyl-4-(diethylaminoalkoxymethyl)piperidine having the formula where X is a lower alkylene radical having from 2to carbon atoms whose two free, valence bonds are on diff ferent carbon atoms, and R2 and R3 are each lower alkyl' radicals, and An is 'a non-toxic anion.

4. -A quaternary ammonium salt of a l-(lower alkyl)- 4-phenyl-4-(dimethylaminoalkoxymethyl)piperidine hav''-.

ing the formula where X'is a lower alkylene radical having from 2m 4 carbon atoms whose two free valence bonds areon clifferent carbon atoms, and R2 and R3 are each lower alky radicals, and An is a non-toxic anion. t

5. A quaternary ammonium salt of a l-(lower alkyl) 4 phenyl-4- tertiary-aminoalkoxymethyl) piperidine having the formula where X is a lower alkylene radical having from 2 to 4 carbon atoms whose two free valence bonds are on different carbon atoms, R2 and R3 are each lower alkyl radicals and An is a non-toxic anion. I

6; A quaternary ammonium salt of a l-(lower alkyl)- 4-phenyl-4-(tertiary-aminoalkoxymethyl)piperidine having the formula where X is a lower alkylene radical having from 2 to 4 carbon atoms whose two free valence bonds are on different carbon atoms, R2 and R3 are each lower'alkyl radicals and An is a non-toxic anion.

7. A quaternary ammonium salt of a l-(lower alkyd) 4-phenyl-4-(tertiary-aminoalkoxy)piperidine having the formula I a R: CHz-CH:

0-X- CH2 Q C CHz- C 2 $Ha (3112 A11 CH: CH:

.i. Ra R: An'

where X is a lower alkylene radical having from 2 to 4 carbon atoms Whose two free valence bonds are on dif-' ferent carbon atoms, R2 and R3 are each ,lower alkyl radicals and An is a non-toxic anion.

8. A dimethohalide of 1-methyl-4-phenyl-4-(Z-dimeth-' ylaminoethoxymethynpiperidine.

9. A dimethohalide of 1-methyI-4-phenyl-4-[2-(1-piperidyl) ethoxymethyllpiperidine.

10. A dimethohalide of l-methyl4-phenyl-4-[3 (l-' piperidyl)propoxymethyllpiperidine.

11. A dimethohalide of 1-methyl-4-phenyl-4-[2-(4- morpholinyl) ethoxymethyl] piperidine.

12. A dimethohalide of lmethyl-4-phenyl-4-[2-(l-piperidyl)ethoxy]piperidine.

13. A process for the preparation of a compound having the formula where n is selected from the group consisting of zero and one, X is a lower alkylene radical having from 2 to 4 carbon atoms whose two free valence bonds are on different carbon atoms, NRR1 is a member of the group consisting of lower dialkylamino, l-piperidyl, (lower alkylated)-l-piperidyl, l-pyrrolidyl, (lower alkylated)-1- pyrrolidyl and 4-morpholinyl, and R2 is a lower alkyl radical, which comprises heating an alkali metal salt of a member of the group consisting of a l-(lower alkyl)- 4-phenyl-4-piperidinol and a l-(lower alkyl)-4-phenyl-4' piperidinemethanol with a tertiary-aminoalkyl halide of the formula halogen-X-NRRr.

14. A process for the preparation of a l-(lower alkyl)- 4-pheny1-4-(dialkylaminoalkoxymethyl)piperidine having the formula i i OH, OH:

where X is a lower alkylene radical having from 2 to 4 carbon atoms whose two free valence bonds are on different carbon atoms and R2 is a lower alkyl radical, which comprises heating an alkali metal salt of a l-(lower alkyl)-4-phenyl-4-piperidinemethanol with a dialkylaminoalkyl halide of the formula halogen-X-N(lower alkyl)2.

15. A process for the preparation of a l-(lower alkyl)- 4-phenyl-4-(tertiary-aminoalkoxymethyl)piperidine having the formula CHr-OH:

16. A process for the preparation of a l-(lower alkyl)- 4-phenyl-4(tertiary-aminoalkoxymethyl)piperidine having the formula OKs-O5: Q /0H:O-X-N o O OHr-O om on: on, /0H:

where X is a lower alkylene radical having from 2 to 4 carbon atoms whose two free valence bonds are on different carbon atoms and R2 is a lower alkyl radical, which comprises heating an alkali metal salt of a l-(lower alkyl)-4-phenyl-4-piperidinemethanol with a tertiary-aminoalkyl halide of the formula OER-OH:

hal0genX-N 0 GHa-OH: 17. A process for the preparation of a l-(lower a1kyl) 4-phenyl-4-(tertiary-aminoalkoxy)piperidine of the forwhere X is a lower alkylene radical having from 2 to 4 carbon atoms whose two free valence bonds are on different carbon atoms and R2 is a lower alkyl radical, which comprises heating an alkali metal salt of a l-(lower alkyl)-4-phenyl-4-piperidino1 with a tertiary-aminoalkyl halide of the formula GE's-0 No references cited.

halogen-XN 

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND HAVING THE FORMULA 